The present invention relates to organometallic complexes based on sterols and diglycerides as novel industrial products.
The invention also relates to pharmaceutical compositions and dietary products containing these complexes.
Acylglycerols, more particularly acylglycerols of fatty acids, are present in the majority of plants and are the main constituents of plant and animal fats.
The only variations from one acylglycerol to another is the number of fatty acids, their position on the glycerol, their chain length and the number and the position of the unsaturated bonds they may contain. In particular, these are mono-, di-, or triacylglycerols.
For both sitosterol and sitostanol, there exists two active isomers, the .beta.-and the .gamma.-isomer. These are also constituents of all plants. In the text, the term sitosterol comprises the beta or the gamma sitosterol (or a mixture of these two isomers), and the term sitostanol comprises beta or gamma sitostanol (or a mixture of these two isomers).
Certain total extracts of plants which, like the majority of plants, contain amongst their very many constituents flavonoids, tannins, saponins, coumarins, alkaloids, triterpenes, sterols, carbohydrates and/or glycosides have been described for their hypoglycaemic activity, such as, for example, acacia extract (Egypt. J. Pharm. Sci., 1992, 33 (1-2), 327-340), or Teucrium oliveranium extract (Fitoterapia, 1984, 55(4), 227-230). No link between the activity and the fraction containing the sterols is established. In these publications, this activity is generally attributed to carbohydrates or polyols of cyclohexane such as condutirol, An inositol derivative isolated from a Gymnema sylvestra extract which does not reduce glycaemia directly, but prevents the sugars from passing through the wall of the intestine.
Some sapogenins have been described for the treatment of diabetes, (sarsasapogenin and similagenin for example, in EP 0 204 661). These are derivatives whose lateral chain is constituted of two cyclic spiro ethers.
Other hypoglycaemic derivatives of plant origin have been described, such as, for example:
the glycoside of leucopelargonidin in Indian J. Exp. Biol. 1993, 31(1), 26-29; PA1 the glycosides of prototimosaponin in Chemical Abstracts 117(9):83451f which is a summary of the Japanese patent JP 04054194; PA1 ginsenoside Rb2 described in Chemical Abstracts 105(17):146237r which is a summary of the Japanese patent JP 61024597. This product tested on the rat acts as an antidiabetic, the dose via the intraperitoneal route being 10 mg/per rat. This dose reduces the glycaemia by 20%. PA1 exogenous insulin, PA1 sulphamides and/or biguanides, PA1 products reducing the absorption of carbohydrates, and PA1 aldose reductase inhibitors, not yet on the market. PA1 the fibrates: they moderately reduce the cholesterol concentration, and more significantly hypertriglyceridaemia; PA1 the statins (HMG CoA reductase inhibitors): they reduce hypercholesterolaemia and have no action on triglycerides. PA1 French patents FR 2 654 620 and FR 2 676 738 which describe organic derivatives of transition metals, of porphyrin structure; PA1 of a cation of a metal (M) in an oxidation state at least equal to 2 useful as a biocatalyst in living metabolism, PA1 of free beta or gamma sitosterol, or a mixture of these two products, or of a plant extract containing same, PA1 of a mono-, di-, or triglyceride corresponding to formula (I): ##STR2## in which: R.sub.1 is an acyl residue of a saturated or unsaturated C.sub.14 -C.sub.24 fatty acid, hydrogen, or a mono-, di-, or trigalactose or glucose; PA1 R.sub.2 is an acyl residue of a C.sub.18 fatty acid having one unsaturated bond, preferably an oleic acid residue, or one of its positional isomers with respect to the double bond (cis-6,7,9,11 and 13) or one of its iso-branched isomers, PA1 R.sub.3 is an acyl residue of a saturated or unsaturated C.sub.14 to C.sub.24 fatty acid, or a hydrogen atom. PA1 of a cation of a metal (M) in an oxidation state at least equal to 2 useful as a biocatalyst in living metabolism, PA1 of sitosterol, of sitostanol or of a mixture of sitosterol and sitostanol, or of a plant extract containing sitosterol, sitostanol or a mixture of sitosterol and sitostanol, PA1 of the diglyceride of formula (I): ##STR3## in which: R.sub.1 is an acyl residue of oleic acid (C.sub.18 :1), PA1 R.sub.2 in an acyl residue of a linear or branched, saturated or unsaturated fatty acid having between 2 and 18 carbon atoms. PA1 vanadium is advantageously in an oxidation state 3,4 or 5, preferably 4, PA1 niobium is advantageously in an oxidation state 4 or 5, preferably 5, PA1 selenium is advantageously in an oxidation state 4 or 6, preferably 4, PA1 molybdenum is in general in an oxidation state between 4 or 6, preferably 3, PA1 chromium is preferably in oxidation state 3, PA1 zinc is preferably in oxidation state 2. PA1 antimony or tin, if it is desired to treat auto-immune diseases which affect particularly the nervous system, for example multiple sclerosis (MS), PA1 gold in auto-immune pathologies affecting the locomotor system, for example in the case of rheumatoid arthritis, PA1 vanadium in neoplasias of the digestive tract, particularly of the pancreas, the colon and the rectum, PA1 ruthenium or palladium in respiratory neoplasias, PA1 lithium in pathologies of the central nervous system, PA1 tin in acquired immuno-deficiency syndromes, may be cited. PA1 olive oil, where the content of oleic acid (C.sub.18 :1) is between 60 and 80%, European oils being richer in C.sub.18:1 than oils from North Africa, PA1 sunflower oil, of the variety known as oleic sunflower hybrid, which contains 83% of C.sub.18:1, instead of the 16% in normal sunflower oil, PA1 safflower oil of the oleic variety which contains 73 to 80% of C.sub.18:1, instead of the 10-20% in the linoleic variety, PA1 almond oil containing 64 to 82% of C.sub.18:1, PA1 hazel nut oil containing 66 to 83% of C.sub.18:1, PA1 avocado oil for which the C.sub.18:1 content ranges from 36 to 80%. PA1 sitosterol and/or sitostanol, more generally the mixture of sitosterol and sitostanol or pure sitostanol are advantageously used in the proportion of 1000 to 10000 mole per mole of metal, PA1 the diglyceride is advantageously used in equimolar proportion with respect to the metal. Even so, these proportions can be such that the diglyceride/metal molar ratio be between 1 and 100. PA1 sitosterol and sitostanol by gas phase chromatography, HPLC or .sup.1 H NMR. PA1 acylglycerol by HPLC, with a light diffusion detector, on a C.sub.18 kromasil column, with an eluent composed of isocratic acetonitrile. PA1 vanadium salts, in development for a decade (vanadyl and vanadate) are active in animals at doses of 5 to 10 mg/kg (expressed as metal) introduced peritoneally; at this dose, they are very toxic, and cannot be administered to man. PA1 certain organic complexes described in recent years, notably in European patent No. 0 305 264, filed the 10th Aug. 1988, enable obtaining an activity at doses of the order of 1 to 5 mg/kg (expressed as metal). PA1 the organometallic complexes of vanadium, described according to the invention, themselves show optimum activity (return to a normal level of glycaemia and most often a lasting cure of all the symptoms), with a dose of vanadium (expressed as metal) of the order of 1 .mu.g/kg in animals; that is at doses much lower (5000 times less) and devoid of toxicity, comparable to the amounts in the daily diet (40 to 60 .mu.g per day in man).
The leaves and flowering extremities of the nettle (Urtica dioica) are known traditionally for their antidiabetic properties (first description in the scientific literature was 1926). This activity is reproducible and quantifiable, but nobody has hitherto isolated the active principle(s).
Plant sterols, particularly those from the root of the nettle (Urtica dioica) have for many years been the subject of many studies, especially for the treatment of certain tumors such as adenoma of the prostate.
A Pygeum africanum plant extract, marketed in France for many years by Laboratoires DEBAT under the trademark of TADENAN.RTM. for the treatment of adenoma of the prostate, has been the subject of recent studies which tend to prove that the activity would be due to the sterol-lipid fraction which contain, according to R. Longo and S. Tyra, Farmaco, Ed. Pract. 1983, 38(7), pages 287-292, beta-sitosterol, beta-sitosteryl glucoside and 3 beta-sitostenone as well as n-docosanol and n-docosyl trans-ferulate, according to Chemical Abstracts CA 104(22): 193255j.
In Journal of Natural Products, 1987, 50(5), pages 881-885, N. Chaurasia and M. Wichtl describe the isolation, the separation, and the identification of certain sterols from the root of the nettle.
In 1979, a team of Brazilian researchers described, in Rev. Med. Univ. Fed. Ceara, 19(1-2), 49-53, a green arabica coffee bean extract of which sitosterol would be hypoglycaemic. Since then, it has not been possible for this activity to be reproduced and no work has been published which confirms it.
U.S. Pat. No. 4,588,717 describes, as vitamin supplement, weight reducer and diet supplement which reduces the absorption of carbohydrates, and therefore glycaemia, a mixture containing metals, metal complexes and fructose, vitamins, fatty acids, phospholipids, esters of sterols, amino-acids, etc.
The authors of this patent do not describe as such the therapeutic activity, they do not attribute the properties of their mixture to any one family of products present in the mixture.
The hypocholesterolaemic virtues of plant sterols have been known for several decades. They reduce cholesterolaemia by inhibiting the intestinal absorption of cholesterol (by co-precipitation or by displacement of the bonds between the micelles). The addition to the diet of large quantities of these sterols, sitosterol in particular, at a daily dose of at least 30 g has been used since the fifties for the treatment of hypercholesterolaemia, but the unpleasant taste and texture of these preparations has been an obstacle to its use. Such activity can only be obtained with large amounts of sitosterol.
Miettinen et al.(New England Journal of Medicine, 1995, vol. 333, n.degree.20, p.1308) have developed a margarine containing an ester of sitostanol. According to these authors, sitostanol greatly reduces the absorption of cholesterol by the intestine. A double blind study was carried out for one year on a population suffering from moderate hypercholesterolaemia. 51 subjects consumed a margarine enriched in sitostanol ester (2.6 g /day). After one year, a reduction of 10% of the total cholesterolaemia and a reduction of 14% in the LDL was observed in these patients. No change in the level of triglycerides nor of HDL was observed. It must be noted however that the study was carried out on a population having a high intake of cholesterol, and the authors doubt that a comparable activity would be observed in subjects whose diet is low in cholesterol, since sitostanol is not absorbed and its activity is confined to the inhibition of the absorption of cholesterol by the intestine.
A hypocholesterolaemic activity has also been described in the animal: Antihypercholesterolaemic activity in rabbits: I. Ikeda et al. J; Nutr. Sci. Vitaminol., 27, 243, 1981. They add, to the rabbits' food, cholesterol and sitosterol or sitostanol (at the dose of 0.5% and 0.2%). Sitostanol inhibits the rise in plasma cholesterol content better than sitosterol. The authors conclude that the hypocholesterolaemic activity of sitostanol results from the inhibiting effect of the absorption of cholesterol by the intestine.
No treatment at present exists for correcting hyperinsulinism and its metabolic consequences, except for a Mediterranean type diet and regular muscular physical activity.
Furthermore, diabetes is controlled or contained by products which regulate glycaemia:
None of these treatments really treats the causes of diabetes, nor do they cause a truly long-term remission, nor a cure which persists after stopping the treatment.
The treatment of dyslipidaemia is at present based on two types of treatment:
These two types of treatment of hypercholesterolaemia and of hypertriglyceridaemia are employed more and more since it is now considered that a reduction of 10% in the level of cholesterol results in a reduction of 20% in the risk of heart disease; they are very often poorly tolerated by patients in which they cause painful effects on the muscles.
Various patents have described different associations, in particular in the form of organometallic complexes which can be used for the treatment and/or prevention of hyperglycaemia, of diabetes and of associated conditions.
French patent FR 2 659 333 which describes derivatives of phospholipid structure;
French patent FR 2 686 600 which describes organometallic complexes of inositol, or of its derivatives;
French patent FR 2 686 511, which describes some complexes of aminoacids;
French patent FR 2 686 512, which describes some organometallic complexes with catechol derivatives;
French patent FR 2 686 514, which describes some organometallic complexes in which the ligand contains a cyclic structure containing at least two nitrogen atoms;
French patent FR 2 686 603, which describes some organometallic complexes with dithiocarbamic acid derivatives; and
French patent FR 2 686 515 which is more particularly directed towards the use of organometallic derivatives of niobium for the treatment and prevention of disorders in the metabolism of glucides and/or lipids, are cited.
Furthermore, the French patent application FR 2 695 390 describes pharmaceutical compositions containing complexes of tannins with various metals.